Total Digital Recall VLDL Reelin Receptor Dab1 Reelin L How We Store Our Memories Is Still a Mystery

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Reelin Daedalus CR CR Total digital recall VLDL Reelin receptor Dab1 Reelin L How we store our memories is still a mystery. The secret seems to lie in the DL VL VL or rec DL recept epto synapses where a dendrite from one brain E-R2 Co-R ApoE r Apo Reelin -R2 ApoE-R2 cell touches the axon of another. But the ? R? information may be recorded physically, Dab1 Dab1 via the growth of new synapses; or NPXY NPXY . . . chemically, via the synthesis of special encoding substances. These alter the chance that the synapse will convey a a b Cortical patterning c C ortical patterning nervous impulse from one neuron to the other, or the chance that the receiving Figure 1 Lipoprotein receptors and the Reelin signalling pathway. a, In the developing cortex, neuron neuron will fire under this stimulation. precursors (black ovals) give rise to immature, elongated neurons that migrate (black) to settle in the To settle the matter by experimenting cortical plate (green). This area is bordered externally by Cajal–Retzius cells (CR; red), which secrete on living brains is daunting, and maybe Reelin, and internally by the subplate (pink). Patterning of the cortical plate depends not only on Reelin, unethical as well. So Daedalus plans to but also on proteins expressed in the cortical-plate cells — Dab1 and, according to Trommsdorff et al.2, study the information content of dead the VLDL receptor and the ApoE-R2. b, The VLDL receptor and ApoE-R2 could react to the presence of ones. Already organizations exist which Reelin or Reelin fragments by docking Dab1 through their NPXY cytoplasmic sequence. A co-receptor will freeze your corpse in liquid nitrogen, (Co-R) to Reelin could also be present. c, Reelin could act on an unidentified Reelin receptor and, via and store it until science is sufficiently Dab1, recruit the VLDL receptor and ApoE-R2. Then, the VLDL receptor and ApoE-R2, together with advanced to thaw you out and restore you an associated putative extracellular ligand (L), could direct cortical patterning. to life. If you cannot afford a whole-body cryogenic crypt, you can merely have your LDLR-related protein. Apparently, the other receptors to Reelin or fragments of this pro- head stored instead. In due course, science three members of this family do not share the tein10. By docking Dab1, these receptors then will then have to give you a new body. effects of the VLDL receptor and ApoE-R2 modulate associated tyrosine kinase(s), and Alternatively, says Daedalus, it might be on brain development. instruct the patterning of neurons at the end possible to read all the information in your The best-known ligand for the VLDL of migration. A variant of this explanation is dead and frozen brain. The totality of your receptor and ApoE-R2 is apolipoprotein E that the VLDL receptor and ApoE-R2 could experience would thus be captured for (ApoE). Although this protein is synthesized bring Dab1 to a Reelin co-receptor that has an posterity — a rather second-class form of in the brain — probably in glial cells — it is associated tyrosine kinase activity. The main immortality, but better than nothing. unlikely to be critical in the Reelin pathway, difficulty with this model is that, as far as DREADCO physiologists are now because mice that lack ApoE develop normal- we know, nobody has yet shown a physical working out how to do it. They propose ly. As well as ApoE, lipoprotein receptors can association between the VLDL receptor/ sectioning the frozen brain into micron- bind thrombospondin-1, lipoprotein lipase, ApoE-R2 and Reelin or Reelin fragments. thin slices with a cryogenic microtome. the serine protease urokinase-type plasmino- A different view (Fig. 1c) is that the VLDL Each slice will be scanned by electron gen activator and probably others. The ligands receptor/ApoE-R2 could act downstream of microscope, and recorded as a digitized implicated in patterning the embryonic brain Reelin and Dab1. Lipoprotein receptors are image. The resulting 100,000 images will have not, however, been defined thus far. involved in cellular uptake so they could, be stored in a terabyte memory, and used The fascinating finding that Reelin, Dab1 for example, modify membrane trafficking, to reconstruct the complete synaptic and the VLDL receptor/ApoE-R2 participate thereby shaping the normal characteristics of ‘wiring diagram’ of the brain. Its chemical in the same genetic pathway fits nicely postmigratory neurons. As yet, though, the map will be harder to recover. Each slice with previous observations. For instance, putative Reelin receptor, its interaction with will have to be treated with fluorescent Dab1 interacts with the cytoplasmic tail of Dab1, and the ligand(s) for the lipoprotein immunoassay reagents binding to the lipoprotein receptors and binds directly to receptor remain to be characterized. crucial encoding substances, so as to the NPXY sequence, which has been impli- Whichever model (if either) is correct, both record their distribution in the slice. cated in lipoprotein-receptor-mediated cel- point to the necessity to identify and define Daedalus cheerfully admits that the lular uptake8,9. The Dab1 protein also docks putative Reelin receptors. This task will not be resulting vast mass of data will be utterly to the cytoplasmic signalling protein Ship, to any the easier if the processing of Reelin into incomprehensible. But, as with the steadily some phosphatidyl inositols, as well as to the fragments, which has now been confirmed by growing incomprehensible data of the ȋ-amyloid precursor protein and related several groups, is functionally important. human-genome project, we must hope that proteins (ref. 9; R. Homayouni and T. Cur- Isabelle Bar and André M. Goffinet are in the one day it will all make sense. In due course ran, personal communication). The ȋ-amy- Neurobiology Unit, University of Namur Medical science will advance enough to interpret loid precursor protein is cleaved to form the School, 61 rue de Bruxelles, B5000 Namur, Belgium. your stored brain map — when your amyloid deposits in Alzheimer’s disease. e-mail: [email protected] heroic sacrifice will finally bear fruit. Every Moreover, the ApoE4 allele is associated with 1. D’Arcangelo, G. et al. Nature 374, 719–723 (1995). detail of your life will be recovered, as a an increased predisposition to this disease. 2. Trommsdorff, M. et al. Cell 97, 689–701 (1999). fascinating historical record. Secrets you 3. Lambert de Rouvroit, C. & Goffinet, A. M. Adv. Anat. Embryol. So, these observations might have patho- Cell. Biol. 150, 1–106 (1998). took to the grave will be revealed at last. physiological implications. 4. Howell, B. W. et al. Nature 389, 733–737 (1997). And if the data can by then be inserted Although several pieces of the puzzle are 5. Sheldon, M. et al. Nature 389, 730–733 (1997). back into a living brain, you might live still missing, Trommsdorff and colleagues’ 6. Ware, M. L. et al. Neuron 19, 239–249 (1997). again as a parasitic consciousness within 7. Howell, B. W. et al. Genes Dev. 13, 643–648 (1999). data can be interpreted in at least two ways. 8. Trommsdorff, M. et al. J. Biol. Chem. 273, 33556–33560 (1998). the mind of someone else. The most parsimonious explanation (Fig. 1b) 9. Howell, B.W., et al. Mol. Cell. Biol. (in the press). David Jones is that the VLDL receptor and ApoE-R2 are 10.Lambert de Rouvroit, C. et al. Exp. Neurol. 156, 214–217 (1999).